Atherosclerosis is caused by a chronic inflammation of large arterial blood vessels superimposed upon by hyperlipidemias, as well as other risk factor. The processes involved in the initiation of atherosclerosis are still poorly understood, but there is incontrovertible evidence that autoimmunity, characterized by a T cell response to specific auto-antigens, plays a major role. Currently, one of the more promising methods for the prevention and treatment of autoimmune diseases is to induce antigen-specific T cell tolerance by intravenous treatment with antigen-coupled ethylene carbodiimide (ECDI)-fixed splenocytes. The fixation of splenocytes (or other donor cells) with ECDI in the presence of antigen results in the formation of peptide bonds between free amino and carboxyl groups, which bind the antigen to the cells, generating a antigen carrier system capable of inducing antigen- specific T cell tolerance. Current evidence indicates that tolerance induced by antigen-coupled cells is due, at least in part, to the up-regulation of CD4+CD25+FoxP3+ regulatory T cells (Tregs) that function in the suppression of pathogenic T cells. The goals of this proposal are to determine whether antigen-coupled cells can modulate the development of atherosclerotic lesions in experimental animals. Accordingly, the first objective of this proposal is to determine the effectiveness of tolerance induced by atherosclerosis-specific antigen-coupled cells in: a) preventing the formation of atherosclerotic lesions;b) reducing lesion size and severity, and/or c) causing lesion regression in two well-establish murine models of atherosclerosis: the low-density lipoprotein receptor deficient mouse (LDLR-/-) and the apolipoprotein E deficient mouse (apoE-/-). The second objective is to investigate the effect of tolerance on atherosclerosis antigen-specific T cell and antibody responses focusing on whether antigen-specific Tregs play a significant role in the prevention of atherosclerotic lesions in this tolerance model. PUBLIC HEALTH RELEVANCE: Atherosclerosis and its complications are a major public health problem, accounting for over half the annual mortality in the United States. This disease begins, at least in part, as a result of an autoimmune reaction in the major arterial blood vessels. In this application we propose to examine whether this autoimmune reaction can be neutralized thereby preventing or causing the regression of atherosclerosis in animal models of this disease.